Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Gu, Hongmei, Fisher, Amanda J., Mickler, Elizabeth A., Duerson, Frank, III, Cummings, Oscar W., Peters-Golden, Marc, Twigg, Homer L., III, Woodruff, Trent M., Wilkes, David S. and Vittal, Ragini (2016) Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB Journal, 30 6: 2336-2350. doi:10.1096/fj.201500044

Author Gu, Hongmei
Fisher, Amanda J.
Mickler, Elizabeth A.
Duerson, Frank, III
Cummings, Oscar W.
Peters-Golden, Marc
Twigg, Homer L., III
Woodruff, Trent M.
Wilkes, David S.
Vittal, Ragini
Title Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis
Journal name FASEB Journal   Check publisher's open access policy
ISSN 1530-6860
Publication date 2016-06-01
Year available 2016
Sub-type Article (original research)
DOI 10.1096/fj.201500044
Open Access Status Not Open Access
Volume 30
Issue 6
Start page 2336
End page 2350
Total pages 15
Place of publication Bethesda, MD United States
Publisher Federation of American Societies for Experimental Biology
Language eng
Formatted abstract
Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxins—complement component 3a (C3a) and complement component 5a (C5a)—in IPF, which interact with TGF-β and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycin-injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson’s trichrome, hydroxyproline, collagen type I α 1 chain, and collagen type I α 2 chain). Pharmacologic or RNA interference–specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5b-9) locally and active TGF-β1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn. Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5b-9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGF-β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.
Keyword C5b-9
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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